This application is for a Clinical Trial Pilot Study (R34) entitled Interleukin-1 blockade in recently decompensated heart failure submitted by Antonio Abbate MD, PhD and Benjamin Van Tassell, PharmD. Heart failure (HF) is a complex clinical syndrome characterized by fatigue and labored breathing upon exertion. Although current treatment options have extended life expectancy, prognosis for HF remains poor and HF is the leading cause of admission among elderly patients in the US. There is an urgent need to develop novel treatments to alleviate symptoms, slow disease progression, and reduce HF hospitalization. A significant correlation exists between declining cardiac function and increasing levels of inflammatory cytokines in HF patients. Among these cytokines, Interleukin-1 (IL-1) is a key mediator of systemic inflammation that becomes elevated in HF patients and may contribute to poor cardiac function. In animal models of HF, IL-1 is sufficient to cause significant depression of cardiac function, impaired cardiac reserve, and worsened cardiac remodeling. In a recent proof-of-concept study, 2 weeks treatment with recombinant human IL-1 receptor antagonist (IL-1Ra, anakinra) produced a significant improvement in aerobic exercise performance as measured by peak oxygen consumption (VO2) and ventilator efficiency (VE/VCO2 slope). We will conduct a randomized, double-blind, pilot study (n=60) to confirm the effect of IL-1 blockade to improve exercise capacity in HF patients and estimate the potential benefit of IL-1 blockade o HF readmission in patients with recently decompensated heart failure (HF). Eligible patients will be randomized to 12 weeks treatment with anakinra (n=20), 2 weeks treatment with anakinra (+10 weeks placebo treatment, n=20), or 12 weeks placebo treatment (n=20). Results from this pilot study will be used to optimize the treatment strategy and design a subsequent phase III clinical trial to evaluate long-term morbidity and mortality with IL-1 blockade in HF patients.